Project Summary The rates of obesity, which is defined as an excessive increase in white adipose tissue (WAT) mass, has increased rapidly over the last several decades and today 65% of the adult population in the U.S. is overweight with more than 30% of the population meeting the criteria for obesity. As the weight of the nation has increased, so have the incidences of many obesity-linked disorders, such as diabetes, cardiovascular disease and certain types of cancer. Despite the importance of WAT in normal physiology and disease, we understand little of the cellular and molecular mechanisms that regulate WAT mass in vivo. WAT is composed of several subcutaneous and visceral depots that are pertinent to the study of obesity. The differential accumulation of excessive WAT in specific depots is associated with differential risks of developing diabetes and other obesity-associated pathologies. However, the mechanisms that control WAT mass in distinct depots is not well understood. Therefore, establishing the differences in cellular and molecular events that regulate WAT mass in separate WAT depots will lead to a better understanding of obesity and how excessive WAT leads to the development of secondary pathologies. Adipocyte number increases in obesity, but this increased adipocyte number is maintained even after extreme weight loss. We have recently determined there is an obesity-specific mechanism of adipogenesis. The objective of this proposal is to determine the mechanisms that govern adipocyte formation in different physiologically relevant contexts. We hypothesize that distinct regulatory mechanisms control depot-specific adipogenesis in development and obesity. There are numerous conditions that are known to affect WAT mass and function, such as sex and anatomic location. The specific mechanisms that drive adipocyte formation in these different contexts likely influence the function of the resulting adipocytes, impacting their contribution to normal physiology and disease. Here we will define the mechanisms that drive adipocyte hyperplasia in both males and females, building a base of knowledge for future studies of the physiologic impact of these aberrant forms of adipogenesis. These studies may lead to the development of novel, sex-specific strategies for prevention and treatment of obesity and obesity-associated diseases.